Furane amido ketone compounds



Patented Apr. 3, 1951 2,547,713 FURANE AMI-D KETONE COMPOUNDS Loren M. Long,

las

Grosse Pointe Woods, and Nicko- D. Jenesel, Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application March 9, 1950,

Serial No. 148,754

7 Claims. (Cl. 260-345.)

This application is a continuation in part of ourco-pending application, SerialNo. 83,769, filed March 26, 1949, and the invention relates to certain new amide ketones and to methods for 'obtaining the-same. More particularly, the invention relates to amido ketones-of the furane series having the formula.

I 1 o i T'HAe i R" O '(i-CH-CHzO'R or a lower where R, R and Acyl have the same significance as given above.

The first step ofourprocess comprises condensing a 2-furyl acylamidomethyl ketone with formaldehyde in the presence of an alkaline condensation catalyst to obtain the corresponding 2- furyl-w-acylamido-;9-hydroxyethyl ketone. In carrying out this condensation the formaldehyde may .be supplied to the reaction mixture in a number of different'forms. For example, formaldehyde gas, aqueous or alcoholic solutions of formaldehyde, tparaformaldehyde andnther formaldehyde-yielding polymers may be used. In most cases it has been found preferable to use an excess of formaldehyde, usually up to' about 4 or 5 mols, in order to insure completeness of the condensation reaction. A variety of solvents, alkaline condensation catalysts and reaction conditions may also be employed. vAs solvents, either aqueous or anhydrous lower aliphatic alcohols are 2 particularly advantageous but moist dialkyl ethers and dioxane water mixtures may also be used. The alkaline condensation catalyst used in this-phase of the invention may be organic bases, inorganic bases or inorganic salts of acidic or pseudo-acidic organic compounds. Some representative types of these catalysts are the hydroxides, oxides, carbonates, bicarbonates and amides of alkali or alkaline earth metals; alkali metal alko'x'ides; alkaline earth al'koxid'es; alkalimetal phenolates; alkali metal salts of lower aliphatic carboxylic acids; organic tertiary amines and quaternary ammonium hydroxides of organic'tertiary amines. In general, the weakly alkaline catalysts such as sodium bicarbonate, potassium bicarbonate, calcium hydroxide, pyridine, triethylamine, N-ethylmorpholine, N,N-dimethylaniline and the "like are preferred since they make the reaction much easier to control. When strongly alkaline catalysts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium methylate, sodium ethylate and the like are used, care must be taken to remove or inactivate the catalyst as soon as the reaction is completed in order'to prevent the conversion of the desired product to the corresponding methylene bis compound by a dehydration and coupling reaction. Although the amount of catalyst is not critical and can vary from a few hundredths or thousandths of a mol to 1 mol or more, it is preferable from the standpoint of yields-to use only enough to bring about a relatively rapid reaction. In most cases 0.05 mol or less is sufficien't.

The temperature used in carrying out. this methylolation reaction as well as the time required for its completion varies with the catalyst used. In general,the reaction can be carried out at a temperature between about 0 and C. in a time varying from a few minutes to several hours. When strongly alkaline catalysts are used, the reaction proceeds very rapidly and is usually complete in a few minutes at room temperature or below. However, when mildly alkaline catalysts are employed, the reaction is not so rapid and usually requires from about fifteen minutes to several hours at room temperature of slightly above, that is, at about 25-50 C.

The conversion of the -2-furyl-a -acylamido-flhydroxyethyl ketone compounds to the corresponding fl-acyloxy derivatives shown by the second step in the above diagram can be effected by treating the fi-hydroxy ketone compound with an acyl halide or acyl anhyd'ride under substantially anhydrous conditions either alone or in the presence of an acylation catalyst such as an inorganic base, an alkaline salt of an organic acid, an organic tertiary base, an aromatic sulfonic acid or sulfuric-acid. The acylation can, in general, be carried out at a temperature varying from about to 140 C. but the preferred temperature for the reaction is between about 60 and 120 C. An inert organic solvent such as benzene; petroleum ether, toluene and the like can be used for the reaction, if desired, although in most instances it is preferable merely to use an excess of the acylating agent. Some of the catalysts which can be used to bring about the reaction in a shorter period of time are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate, pyridine, quinoline, triethylamine, N- I ethylmorpholine, N-ethylpiperidine, N,N-dimethylaniline, p-toluenesulfonic acid and sulfuric acid.

The products of the invention are useful in the preparation of other organic compounds. They are of particular value in the preparation of organic compounds possessing antibiotic activity against microorganisms of the Rickettsia type.

The practice of our invention is illustrated by the following examples.

Example 1 Example 2 12 g. of Z-furyl a-acetamido-,B-hydroxyethyl ketone is added to cc. of acetic anhydride and 0.1 cc. of concentrated sulfuric acid added to the mixture. The reaction mixture is heated at 60 C. for one-half hour, cooled and evaporated to dryness in vacuo. The residue is treated with water, the insoluble 2-furyl a-acetamido-fi-acetoxyethyl ketone collected, washed with a small amount of water and dried. The formula of this product is,

0 o NH-PJ-CHa -orL-omoo-om Example 3 '13 g. of 2-furyl dichloroacetamidomethyl ketone is dissolved in 350 ml. of methanol and 100 ml. of 40% formalin and 3.5 g. of sodium bicarbonate is added to the resulting solution. After stirring for one and one-half hours at room temperature, the solution deposits crystals of the desired product. The 2-furyl a-dichloroacetamidofl-hydroxyethyl ketone is recrystallized from ethyl acetate. This compound has the formula,

E EHCOCHCh o H-CHgOH Example 4 formula,

0 NIT-E- O I O C-CE-CHgOH Example 5 20 g. of 5-chloro-2-furyl crotonamidomethyl ketone is dissolved in a solution of 200 ml. of

methanol and 35 ml. of 40% formalin. After the addition of 1 g. of sodium bicarbonate, the solution is stirred at room temperature for one and one-half hours. The solution is evaporated to about ml. whereupon some solid separates. Dilution of the resulting solution with water elfects the precipitation of 5-Oh10l1'O-2-flllY1-acrotonamido-B-hydroxyethyl ketone, which is collected, washed free of formalin with water, and recrystallized from aqueous dioxane. This compound has the formula,

Example 6 crystallized from ethyl acetate. This compound has the formula,

0 Net b. 12 g. of 5-bromo-2-furyl a-nicotinamido 'phydroxyethyl ketone is added to 30 ml. of acetic anhydride, and 0.1 ml. of concentrated sulfuric acid is added to the mixture. The mixture is heated at 50 C. for one and one-half hours, then evaporated to dryness in vacuo. Treatment of the residue with water leaves an insoluble residue which, after two recrystallizations from ethyl acetate, is found to be 5-bromo-2-furyl a-nicotinamido-fi-acetoxyethyl ketone which has the formula.

precipitate-1mm aqueous 'iethanolzyields iii-nit ie-caniste 1103.332 of isnltro2furyl idio'lilotoect d0- methylcketone'isidissolveddnAoflzliilhdtmethanol .containingM125 m1. iQf A0372, .iormalinLand- 4333. of sodiunr'blcarbonate. iiflheeresulti-ngeso 11151011 deposits, -duringcstirringafor fllliqminiitesgae'solid which, rafter recrystallization ;;from :aqueous ethanol, found :to she B-nitre-I'Zfiurifil memoroacetamidose hslxiroxyethsil i-ketone. 'TZIhe x'iiormula-zof this compoundis,

mg. of amne ia-mm raeetaminomethyl ketoneiisimixed with 4500 50c. ofsmethanol sand 15.0 cc. of. 40%iorma1in. 51g.ofisodium'bicaizbonlte is added :and itheimixture .Xstirre'di at.,room .temperature for about onelhour. .DuringIJthisTtime the desired solid product separates. flThe, product Liscollected and Tpurified bymecrystallizati from ethyl acetate.

:ketone which 4 has theyfollowing formula,

'Thevwmaterial-.thusohta;ined

imam araquebussalcehol. i Th'eiiforw miilaic'itlthistcnmifloundiis; 1 1 x b. 23 g. of 5-methyl-2-fury1 a-acetoxyacetamido-fi-hydroxyethyl 'ketcne' ini 100 ml. of pyridine sis-treatedwith.40 .m1. of benzoyl chloride. .Con- .gcentrationiof the solutionsin vacuoigives anloil whichssolidifies on i-additio'n of water. Theiisdlid isnc'ollected, washed with wateneandrecrystallized from ethyl acetate. 'The desired *5eme'th5z'li2- mm sa-iacetoxyacetamido p-bienaoxyethyl ktone has thelfiormul'a,

Example -12 g. of 5-methyl-2-furyl 2'-furamidomethyl ketone, 150 ml. of methyl alcohol, 30 ml. of formalin, and -1-1g. of sodium bicarbonate are stirred together for :onehour at room tempera- --ture. :Addition of water to the solution effects and 0,2;m1. ioficoncentrated'lasiiliuricaeicid I heated :at' BD" C. Ior 30 :minutes. -.-Addition f waterto ithetsolution rand ireerystallizatiom-v'of-i 2 furyli-dichloroacetamido-fi acetoxyethyl he: tone which has the formula,

0 Q 5 '0 "mi d- 01101, 15

ozN U osca-1021110 c-cm Exempted?!) '50 A mixture consisting of ease.:erimmemylizfurylphenylactamido ktone,a g; 5: "carhonafte "and 80- cc.-of1,4U% formal $111135 cc. of metli'anol is warmed 'fi'at EC. :Lformne- "11 hour. The reaction mixture is allowed to at room temperature for about onehour and poured .into 3 liters :of ice water. The precipi tated productlis rcollected, washed With waterndi purified-byrecrystallization from ethyl aceta obtain the pure 5-methyl-2-i1iny1'aeaphenyla. amide-H hydroxyethyl iketone'iof iiormula, v

precipitation of thevdesired 5-methyl-2-furyl a- 2 --uramidoefiehydroxyethyl ketone which 151C01- lected wand .1:ecrysta1lized from *aqueous ethanol. The'i'iormulai forxthisumateria-l is,

Example 13 4 g. of 5-methyl 2-furyl r'nethoxyacetamidomethyl ketone isdissolvedin' a mixture "of '50 ml. of methanol, 10 nil; of 40% formalin and OJI- g; or 'sodium'bicarbonate and stirred'at room temperature7foi 3'0' minutes. 'Dilution of the r'solution' with Water'causes precipitation of the 'des'ire'd fi-metm ketone which canhe recrystallized from aqueous dioxane. This compound has the formula,

Example 14 a. 43.1 of 5-ethyl-2-furyl bromacetamidomethyl heme in 155 ml. of methanol vis "treated WithQ m1. of A'Ol% iormeilin and? g. of sodium bicarbonate. After stirring for one hour'a'tioo'm temperature, the'solution i s5po11red intowa'ter whereupon the desired l5-ethy1-l2-Jfuryl a-brom'e iacetamido-ifi-hydroxyethyl'ketoneseparates as an oil. compound has the formu'la,

.0 (Lo Nero-carer ems I-H-OHzOH 'b. 40 g. of 'fi-ethyl-zfuryl a-bromac'etami'do-fihydroxyethyl ketone' inf nil. of pyridine is treated with f? of p-toluj l "chloride at 40 50 "C. :for onie'antl "one halfhoursi Upon dilution of the soilutron'with volumes of water, the desired ii -ethafb-v furyi 'a bromacetanfido ge p tbluyicxy ethyl ketonef se'pa'ratesiand is .recrystallized;irem

ethyl acetate. This compound has: the-formula;

o oZNH -pHr-Brf z s HL-AZH- QH3 ii Example 15 173 g. of -ethyl-2-furyl phenylacetamidomethyle ketone isstirred for one hour with a mixtureof 790 ml. of methanol, 2 0Q -ml of 4 0% formalin and g. of sodium bicarbonate, Evaporation of the solution to an approximate volume of 200 ml. and'treatment thereofwitfi 2 volumes of hot water efiects separation-cf the desired 5-ethyl-2-furyl d-phenylacetamido-p-hydroxyethyl ketone as the hot solution is allowed to cool. This; compound has the formula,

Example 16 l: r "100 g. of 5-ethyl-2-furyl succinamidomethyl ke tone in o ml. of methanol is treated with' 170 ml. of 49% formalin and 4 g. of sodium bicarbon ate.' Concentration of the solution in vacuo e'f fects' precipitation of the a succina'nlido'-p-hydroxyethyl ketone which is collected, washed with water andrecrystallized from ethyl acetate. This compound has the formula, 5 F

o Nuii CHP BF-G 02H cm 0 -cn-om'on Eaample e 91 g. of -5-ethyl-2-furyl cyanoacetamidomethyl ketone'and 130 m1. of 40% formalin in 400 ml. of methanol are treated with 5 g. of sodiumbicar; bonate for one hour at room temperature. -Di1utiOn ,of the mixture with 2 volumes of water efiects precipitation of the desired -5-ethyl-2-furyl cyanoacetamido-B-hydroxyethyl ketone. I This material is collected and recrystallized f 'e n O o 'N ii-oHQCrI elm -cu-omon 1 The 2-furyl acylamidomethyl ketones used as starting materials in the practice of the invention maybe preparedby the method described in our co-pending application, No. 148,755, ii1e d under even date herewith. Said meth'od consists'; in simultaneously neutralizing and acylat ingan acid addition salt of the corresponding 2-furyl aminomethyl ketone. This processwhich can be diagrammatically depicted as follows:

0 0 RQg-omNm-Hx am omuam l ,where' X is an anion of a'strong inorganic acid and 'R, has the same significance as given above; is carried out by reacting the acidv addition salt of the 2-furyl aminomethyl ketone with an. acylating in the presence-of a basic "catalyst whieh aqueous dioxane. The formula of this compound w l i.

one hour.

desired 5 ethy1-2;fu 1

decompose in situ thegstable -acid addition salt of the. ammo ketpne-u ;;T i lflow 'ne s l mme eerie"ibiil fieif i-i s appH t19npf-thi gene.ra1 met od tothe' preparation foffsonie' 'of" the fspecifle starting materials: us d i heiqr eomse a es e l' aminomethyl ketone hydrochlorideand30 g, of sodium acetate are addedjd about 100 ml, of bis-dichloroacetic an hydride. The solution isstirred at ill-C; for

Upon stirring into water, the solid 5- nitro 2 furyl dichloroacetamidomethyl ketone separates, and is recrystallizedfrom aqueous alcohol. Thisooi'np'oulid has the fojrmula,

A QR IOI" .l cm 0 p+ o- H, --N11-c-o1ioh fist" driififli b i l finii y k hydrochloride is dissolved in a mixture composed of 1 liter of glacialacetic acid and 30 0 ed. '01 aceticanhydride 85g. of sodium acetate is add+ ed in small portions with stirring to the'mixture and after. the addition has been completed the solution is diluted with water. The insoluble 5-nit1jo-2 furyl acetamidomethyl ketone which separatesiiom the solution is collected, washed with a small'amountof water-and dried. The formula of this product is,

- "(Lorraine-(Loni 0 c. 50 g. of 2-furyl: aminomethyl ketone hydrochloride isaddedto a mixture composed of 400cc. of glacial a'ce fe-aeid and 100150. of acetic anhydride.

49 ig s oldiuimfaetat e is added i smallp rujo'ns h stirrmg'and after-'afew minutes" the reaction m xture dilutd with water The insoluble z-ruryi; aeetam'idomethyl ketone" is" collected, washedwitlr'water' and-dried. This product has the fOiIiliiIa;-'

d. g. of 5-methyl-2'-'-furyl "aminomethyl ketone hydrobromide is added to a mixture consisting of '70 g. of dry pyridine and 50 g. of phenyl acetyl chloride, keeping the temperature below about 5"C.-- After stirring; for about-one hour 1 liter;of ,cold water is added and the precipitated product; collectede The product thus obtainedis 5'-methyl- 2 -"fury1'phenylacetamidomethyl ketone What we clafmisz Y 1. A compound of formula,

where R is a member of the class consisting of hydrogen-N02, halpgenandlower alkyl radicals and R is a ember of the class consisting of where R is a member of the chase consisting of hydrogen,-N02, halogen, and lower alkyl radicals.

3. 2-fury1 a-dichloroacetamido-p-hydroxyethyl ketone.

4. 5 nitro 2-fury1a-dichloroacetamldo-p-hydroxyethyl ketone.

5. 5-nitro-2-fury1 a-acetamido-p-hydroxyethy1 ketone.

6; 5 nitro-,2-fury1 a-diehloroacetamido-p-acefioxyethyl ketone.

7. 2-furyl a-acetamido-p-acetoxyethyl ketone.

LOREN M. LONG. NICKOLAS D. JENESEL.

No references cited. 

1. A COMPOUND OF FORMULA, 